In recreational drug use, high but non toxic doses of a drug are occasionally administered. When rats are administered amphetamine according to this kind of regime, an acute withdrawal syndrome occurs approximately 18 to 24 hours after drug receipt. Hypoactivity and hypophagia are among the symptoms observed. The overall research goal is to understand this amphetamine-induced acute withdrawal syndrome. As in past award periods, basic information about the conditions that elicit different symptoms will be sought, and hypotheses about mechanisms involved will be assessed. But in addition, a new theory of how the symptoms of the acute withdrawal syndrome are organized will be explored. According to this theory, the syndrome is organized into symptom clusters, that is, different groups of interrelated symptoms. In most of the proposed experiments, rats will be housed in stations where either activity or food intake can be continuously monitored. In several of the proposed studies, provisional criteria for grouping symptoms will be applied to hypoactivity and hypophagia, in order to assess whether they are components of the same symptom cluster. For example, if different doses of amphetamine produce comparable effects on hypoactivity and hypophagia, then by one criterion the symptoms should be grouped. In other experiments some of the implications of conceiving of the withdrawal syndrome in this way will be assessed. In one study, time-dependent changes in a putative symptom cluster will be used to guide the selection of times at which to look for potential molecular mediators. In a final study, the methodology and conceptualizations will be applied to the acute withdrawal produced by a drug from another class, morphine. The approach used in the proposed studies is consistent with initiatives to classify mental disorders on the basis of observable behaviors and neurobiological measures, rather than on the basis of presenting symptoms. Because the theory under discussion views the fundamental unit of a syndrome as a cluster of symptoms, it has significant implications for diagnosis and treatment. PUBLIC HEALTH RELEVANCE: Acute withdrawal is associated with personal distress, decreased productivity, and increased risk of drug relapse: Consequently, preventing and ameliorating acute withdrawal is an important objective. Acute withdrawal can be managed only if the factors that give rise to the symptoms can be identified. The proposed research will provide an ethical, well controlled, and efficient means for identifying the brain and body factors that contribute to acute withdrawal and for evaluating potential treatments.